Leptospirosis is a paradigm for an urban slum health problem. Rapid urbanization and expanding urban poverty worldwide have created conditions for rat-borne transmission of the Leptospira spirochete. The investigations of Weill Medical College of Cornell University and Oswaldo Cruz Foundation in the city of Salvador, Brazil raised awareness for a new pattern for leptospirosis, characterized by annual rainfall-associated epidemics that occur in slum communities and cause life-threatening manifestations such pulmonary hemorrhage syndrome. The lack of adequate diagnostics and poor understanding of disease pathogenesis are the major barriers to mounting effective public health responses to urban epidemics. We have established active surveillance for leptospirosis in Salvador and performed long-term prospective studies of urban slum populations. These studies raise specific hypotheses on the pathogen, environment and host-related factors in disease transmission. We propose an ICIDR project which applies state-of-the-art approaches in genomics and proteomics to ongoing field investigations for the aim of elucidating the determinants of urban leptospirosis. In the first project aim, we will identify the pathogen factors which influence disease progression and development of pulmonary hemorrhage syndrome using high-throughput genome sequencing of clinical isolates and genetic tools to manipulate Leptospira. In the second project aim, we will develop molecular assays to measure Leptospira in the environment and determine whether such assays can be used to identify transmission sources, stratify disease risk and prioritize prevention in resource-poor settings. In the third project aim, we will use proteome arrays to systematically identify diagnostic and prognostic markers for leptospirosis, as well as potential vaccine candidates. The information gained may lead to novel strategies for intervention, such as targeted environmental control measures, improved diagnostics and vaccines, which are urgently needed as the world's population residing in slums doubles from one to two billion in the next twenty years. Furthermore the ICIDR project will create the translational research capacity in Brazil to address other neglected infectious diseases. RELEVANCE: There is no effective prevention for leptospirosis, a life-threatening bacterial disease which causes epidemics among the urban poor worldwide. The proposed research will apply state-of-the art molecular approaches to field investigations in Brazil for the purpose of characterizing the disease determinants of leptospirosis and identifying novel strategies for intervention, such as improved diagnostics and vaccines.